Peptides with immunomodulatory effects

ABSTRACT

Novel homodimers that include cysteine-containing peptides having 4-15 amino acid residues can be administered to modulate the immune response in an animal.

FIELD OF THE INVENTION

The present invention relates to new peptides, a method for thepreparation of said peptides and a pharmaceutical preparation containingsaid peptides. The peptides according to the present invention areexcellent as immunomodulating agents.

BACKGROUND OF THE INVENTION

There has been a longfelt need for new safe immunomodulatory agents inthe treatment of many different diseases including malignant diseases,autoimmune diseases and asthma/allergy. Present immunomodulatory agentssuch as Cyclosporin A and steroids, are very potent immunosuppressiveagents but also present severe side effects in a dose dependent manner.New immunomodulatory agents with higher specificity for the immunesystem, showing less side effects will be of great benefit in thetreatment of diseases with a pathological immune response as animportant component in the disease process.

PRIOR ART

Signalling between cells are to a major extent mediated by oligo- orpolypeptide principles, including cytokines, neuropeptides and hormones.One possible way such a signal can be transmitted may involveoxidoreductase activity mediated by thiol-disulfide interaction ofcysteine residues. This type of action can induce conformational changesof proteins which ultimately may result in a signal to the cell nuclei.Thus redox systems, based on oxidised or reduced cysteines, playimportant roles in initiating, maintaining and/or downregulatinginflammatory responses. Redox systems that are characterized today arethe thioredoxin (TR)/thioredoxin reductase (TRR) system (Holmgren et al,1989, J.Biol.Chem, 264, 13963) and similar systems like theglutaredoxin/glutathione reductase (Bushweller et al., 1992,Biochemistry, 31, 9288) and the protein disulfide isomerase (PDI)systems (Noiva and Lennarz, 1992, J.Biol.Chem., 267, 3553). The TR/TRRsystem and related redox systems are potent regulators of differentknown immunological and inflammatory parameters, like IL-2R α-chainexpression (Espinoz-Adelgado et al, 1992, J.Immunol., 149, 2961),modulation of expression of IFN-γ activity (Deiss and Kimchi, 1991,Science, 252, 117), differentiation and effector function of lymphocytes(Yodoi and Uchiyama, 1992, Immunol. Today 13, 405-411), regulation ofeosinophil effector functions (Balcewics et al, 1991, J. Immunol., 147,2170), activation of glucocorticoid receptor (Grippo et al, 1985,J.Biol.Chem. 260, 93-97) and modulation of immune response duringpregnancy (Clarke et al, 1991, J.Reprod.Fert., 93, 525).

The active site of TR includes a sequence with a -Cys-Gly-Pro-Cys-motif. Selected virus proteins, e.g. gene products coded from X regionsof human T-cell leukaemia viruses (Shimotohno et al, 1985, P.N.A.S. 82,302-306) and human immunoregulatory proteins may havecysteine-containing sequences which are homologous to such a-Cys-Gly-Pro-Cys- motif. We have considered that these proteins mayeither express oxidoreductase activity or can be substrates for such anactivity or possibly act as inhibitors of such an activity.

Previously peptides based on the cysteine-rich TR active site sequencementioned above have been produced and shown to exhibit biologicalactivities similar to the native protein Another example of acysteine-containing peptide with thioredoxin-like activity was obtainedfrom hFSH-β-(81-95) (Grasso et al, 1991, Molecular and CellularEndocrinology 78, 163).

Analogs of thymic humoral factor γ2 (ThF-γ2) for use as immunomodulatoryagents in pharmaceutical compositions are described in WO, A1, 9501182(12.01.95). This document discloses two cyclic analogs;Leu-Glu-Cys-Gly-Pro-Cys-Phe-Leu (SEQ ID NO: 34) andLeu-Cys-Ala-Gly-Pro-Cys-Phe-Leu (SEQ ID NO: 35);, which are excludedfrom the present invention. However, this document does not reveal theactive importance of cysteine-containing sequences.

We have prepared peptides with cysteine-containing motifs, selected fromvirus structural proteins e.g. retroviral transmembraneous protein p15E,and human proteins involved in regulation of inflammnation, e.g. TGF-β.Peptides were then modified to get optimal immuno-regulatory properties.

OUTLINE OF THE INVENTION

We have now surprisingly found a novel group of peptides which areexcellent as immunomodulators. The peptides according to the presentinvention comprise 4-15 amino acids and can be described by the generalformula (I):

    A-X-Y-Cys-Z-B                                              (I)

wherein

X is selected from Gly, Ala, Ile, Asp, Thr, Ser, Arg or Trp;

Y is selected from Pro, pipecolic acid (hereinafter called Pec) or Ile:

Z is selected from Ile, Phe, Pro, Ala, Tyr or Gly;

A is H, a protecting group, an amino acid in either L- or D-form with orwithout protected sidechain-functionality and/or N-terminal protectionor an amino acid sequence with or without protectedsidechain-functionalities and/or N-terminal protection;

B is OH, NH₂, a protecting group, an amino acid in either L- or D-formwith or without protected sidechain-functionality and ending with aC-terminal amide, a free carboxyl or a protecting group or an amino acidsequence with or without protected sidechain-functionalities and endingwith a C-terminal amide, a free carboxyl or a protecting group; andprovided that the following sequences are excluded from the formula (I):

Leu-Glu-Cys-Gly-Pro-Cys-Phe-Leu (SEQ ID NO: 34),

Leu-Cys-Ala-Gly-Pro-Cys-Phe-Leu (SEQ ID NO: 35),

Tyr-Ile-Pro-Cys-Phe-Pro-Ser-Ser-Leu-Lys-Arg-Leu-Leu-Ile (SEQ ID NO: 36),

Tyr-Ile-Pro-Cys-Phe-Pro-Ser-Ser-Leu-Lys-Arg-Leu-Ile (SEQ ID NO: 37),

Ser-Gly-Pro-Cys-Pro-Lys-Asp-Gly-Gln-Pro-Ser (SEQ ID NO: 38) and

Thr-Pro-Pro-Thr-Pro-Cys-Pro-Ser (SEQ ID NO: 39).

The length of A and B can vary, as long as the criteria concerninglength and possible amino acids or other substituents are fulfilled.

The amino acids according to the present invention can be both naturallyoccurring amino acids and non-naturally, synthetic amino acids or aminoacid analogues.

Examples of protecting groups for A are a variety of carbamates andamides of which the following protecting groups are preferred: acetyl(Ac), 9-fluorenylmethyl carbamate (Fmoc), 1-methyl-1-(4-biphenylyl)ethylcarbamate (Bpoc), trityl (Trt), allyl carbamate (Alloc) and t-butylcarbamate (Boc).

Especially preferred protecting groups for A are acetyl (Ac),9-fluorenylmethyl carbamate (Fmoc) and t-butyl carbamate (Boc).

Examples of protecting groups for B are a variety of esters such as C₁-C₆ alkyl, allyl, adamantyl, benzyl, and t-butyl.

Also within the scope of the present invention are homodimers accordingto the formulae (II), (III) and (IV) ##STR1## i.e. homodimers of thepeptides of the formula (I) according to the invention.

Also within the scope of the present invention are pharmaceuticallyacceptable salts of peptides of the formulae (I), (II), (III) and (IV).

Peptides of the formula (I) containing several cysteine residues mayexist both in an oxidized and in a reduced form. The oxidized form maycontain intramolecular disulfide bonds resulting in oxidized monomers orintermolecular disulfides resulting in both head to head and head totail dimers of the peptides of formula (I).

Preferred peptides according to the present invention are peptides ofthe formulae (I), (II), (III) and (IV) wherein

X is Gly, Y is Pro and Z is Ile;

X is Gly, Y is Pro and Z is Gly;

X is Ala, Y is Pro and Z is Ala;

X is Ile, Y is Pro and Z is Tyr;

X is Ala, Y is Pro and Z is Ile;

X is Arg, Y is Pro and Z is Ile;

X is Ile, Y is Pro and Z is Ile;

X is Asp, Y is Pro and Z is Ile;

X is Trp, Y is Pro and Z is Ile;

X is Trp, Y is Pro and Z is Gly;

X is Gly, Y is Ile and Z is Ile;

X is Gly, Y is Pec and Z is Ile;

X is Thr, Y is Pro and Z is Tyr;

X is Thr, Y is Pec and Z is Phe;

X is Ala, Y is Pro and Z is Phe;

X is Ser, Y is Pro and Z is Phe;

X is Gly, Y is Pro and Z is Pro; or

X is Gly, Y is Pro and Z is Tyr;

wherein A and B can be varied as defined above; and

provided that the following sequence is excluded from the formulae (I),(II), (III) and (IV): Ser-Gly-Pro-Cys-Pro-Lys-Asp-Gly-Gln-Pro-Ser (SEQID NO: 38).

Preferred peptides according to the invention are

H-Gly-Pro-Cys-Ile-OH (SEQ ID NO: 1);

Fmoc-Gly-Pro-Cys-Ile-OH (SEQ ID NO: 1);

H-Gly-Pro-Cys-Gly-OH (SEQ ID NO: 2);

H-Ala-Pro-Cys-Ala-OH (SEQ ID NO: 3);

H-Ile-Pro-Cys-Tyr-OH (SEQ ID NO: 4);

H-Trp-Pro-Cys-Gly-OH (SEQ ID NO: 32);

H-Phe-Gly-Pro-Cys-Ile-OH (SEQ ID NO: 5);

H-Gly-Pro-Cys-Ile-Leu-Asn-NH₂ (SEQ ID NO: 6);

H-Gly-Pro-Cys-Ile-Leu-Asn-Arg-OH (SEQ ID NO: 7);

H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-OH (SEQ ID NO: 8);

H-Leu-Leu-D-Phe-Gly-Pro-Cys-Ile-OH (SEQ ID NO: 8);

H-Leu-Leu-Phe-Ala-Pro-Cys-Ile-OH (SEQ ID NO: 9);

H-Leu-Leu-Phe-Arg-Pro-Cys-Ile-OH (SEQ ID NO: 10);

H-Leu-Leu-Phe-Ile-Pro-Cys-Ile-OH (SEQ ID NO: 11);

H-Leu-Leu-Phe-Asp-Pro-Cys-Ile-OH (SEQ ID NO: 12);

H-Leu-Leu-Phe-Trp-Pro-Cys-Ile-OH (SEQ ID NO: 13);

H-Leu-Leu-Phe-Gly-Ile-Cys-Ile-OH (SEQ ID NO: 14);

H-Leu-Leu-Phe-Gly-Pec-Cys-Ile-OH (SEQ ID NO: 15);

H-Ala-Val-Trp-Thr-Pro-Cys-Tyr-OH (SEQ ID NO: 33);

H-Tyr-Phe-Tyr-Thr-Pec-Cys-Phe-OH (SEQ ID NO: 16);

H-Phe-Val-Met-Ala-Pro-Cys-Phe-OH (SEQ ID NO: 17);

H-Leu-Leu-Tyr-Ser-Pro-Cys-Phe-OH (SEQ ID NO: 18);

H-Ile-Ser-Gly-Pro-Cys-Pro-Lys-OH (SEQ ID NO: 19);

H-Phe-Leu-Phe-Gly-Pro-Cys-Ile-OH (SEQ ID NO: 20);

H-Leu-Phe-Gly-Pro-Cys-Ile-Leu-NH₂ (SEQ ID NO: 21);

H-Glu-Lys-Gly-Pro-Cys-Tyr-Arg-OH (SEQ ID NO: 22);

H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-OH (SEQ ID NO: 23);

H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-NH₂ (SEQ ID NO: 24);

H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-OAllyl (SEQ ID NO: 23);

H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-NH₂ (SEQ ID NO: 25);

H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-OH (SEQ ID NO: 26);

H-Phe-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-NH₂ (SEQ ID NO: 27);

H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-Leu-Met-Glu-NH₂ (SEQ ID NO:28);

H-Phe-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-Leu-Met-Glu-NH₂ (SEQ ID NO:29);

Fmoc-Phe-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-Leu-Met-Glu-NH₂ (SEQ ID NO:29);

H-Phe-Cys-Leu-Gly-Pro-Cys-Pro-OH (SEQ ID NO: 30); ##STR2##

Especially preferred peptides according to the invention are peptides ofthe formulae (I), (II), (III) and (IV) wherein

X is Gly, Y is Pro and Z is Ile;

X is Ala, Y is Pro and Z is Ala;

X is Ala, Y is Pro and Z is Ile;

X is Asp, Y is Pro and Z is Ile;

X is Gly, Y is Ile and Z is Ile;

X is Gly, Y is Pec and Z is Ile;

X is Ser, Y is Pro and Z is Phe; or

X is Gly, Y is Pro and Z is Pro;

wherein A and B can be varied as defined above; and

provided that the following sequence is excluded from the formulae (I),(II), (III) and (IV): Ser-Gly-Pro-Cys-Pro-Lys-Asp-Gly-Gln-Pro-Ser (SEQID NO: 38).

Especially preferred peptides according to the invention are thepeptides

H-Gly-Pro-Cys-Ile-OH (SEQ ID NO: 1);

H-Ala-Pro-Cys-Ala-OH (SEQ ID NO: 3);

H-Phe-Gly-Pro-Cys-Ile-OH (SEQ ID NO: 5);

H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-OH (SEQ ID NO: 8);

H-Leu-Leu-Phe-Ala-Pro-Cys-Ile-OH (SEQ ID NO: 9);

H-Leu-Leu-Phe-Asp-Pro-Cys-Ile-OH (SEQ ID NO: 12);

H-Leu-Leu-Phe-Gly-Ile-Cys-Ile-OH (SEQ ID NO: 14);

H-Leu-Leu-Phe-Gly-Pec-Cys-Ile-OH (SEQ ID NO: 15);

H-Leu-Leu-Tyr-Ser-Pro-Cys-Phe-OH (SEQ ID NO: 18);

H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-OH (SEQ ID NO: 23); ##STR3##

The most preferred peptides according to the invention are peptides ofthe formulae (I), (II), (III) and (IV) wherein

X is Gly, Y is Pro and Z is Ile,

X is Ala, Y is Pro and Z is Ile;

X is Asp, Y is Pro and Z is Ile;

X is Ser, Y is Pro and Z is Phe; or

X is Gly, Y is Pro and Z is Pro;

wherein A and B can be varied as defined above; and

provided that the following sequence is excluded from the formulae (I),(II), (III) and (IV): Ser-Gly-Pro-Cys-Pro-Lys-Asp-Gly-Gln-Pro-Ser (SEQID NO: 38).

The most preferred peptides according to the invention are the peptides

H-Gly-Pro-Cys-Ile-OH (SEQ ID NO: 1);

H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-OH (SEQ ID NO: 8);

H-Leu-Leu-Phe-Ala-Pro-Cys-Ile-OH (SEQ ID NO: 9);

H-Leu-Leu-Phe-Asp-Pro-Cys-Ile-OH (SEQ ID NO: 12);

H-Leu-Leu-Tyr-Ser-Pro-Cys-Phe-OH (SEQ ID NO: 18);

H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-OH (SEQ ID NO: 23); ##STR4##

We have now surprisingly found that peptides of the formulae (I), (II),(III) and (IV) are excellent as immunomodulators, thus having eitherimmunostimulating or immunoinhibitory effect. The invention thusprovides peptides with advantageous properties for the treatment ofdiseases where an anergy of the immune response or an aberrant immuneresponse or an ineffective host defence can be suspected. Such diseasesinclude chronic bronchitis, where a reduction of the rate ofexacerbations has previously been reported with immune responsemodifiers such as Biostim (Radermecker, M. et al. Int. J. Immunopharmac.10, 913-917, 1988, Scheffer, J. et al. Arzneim Forsch/Drug Res: 41,815-820, 1991), Ribomunyl and BronchoVaxom (Paupe, J. Respiration 58,150-154, 1991) as well as with N-acetylcysteine (See Bergstrand, H. etal J. Free Radic. Biol. Med. 2, 119-127, 1986).

Such diseases also include certain forms of malignant diseases. Thus,numerous research institutes round the world aim at finding ways ofstimulating the immune response in patients with various forms ofmalignant diseases and numerous reviews in the literature deal with thisapproach (Stevenson, F. K. FASEB J 5: 2250-2257, 1991; Melief, C. J. M.Advances in Cancer Research 58: 143-75, 1992, Chen, J. et al.,Immunology Today 14:10, 483-86, 1993). To mention one example patientswith intracranial tumours (gliomas) exhibit a profound decrease inimmunity possibly due to a defect in the secretion of IL-2 as well asthe expression of IL-2 receptors in T cells from these patients(Roszman, T. et al. Immunology Today 12, 370-374, 1991). Moreover, asignificant adjuvant effect in immunotherapy of melanoma and coloncarcinoma has been documented for the immunostimulator Levamisole (VanWauwe, J. and Janssen, P. A. J: Int J. Immunopharmac 13, 3-9, 1991) andimmunotherapy with IL-2 in vivo or treatment of patients lymphokineactivated killer cells with IL-2 ex vivo has caused the regression ofcancer in selected patients (Rosenberg, S. A. Immunology Today 9, 58-62,1988). The malignant diseases where the peptides of the formulae (I),(II), (III) and (IV) can be expected to have advantageous effectsinclude tumours of mesenchymal origin such as sarcomas likefibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma or chordosarcoma, sarcomas like angiosarcoma, endotheliosarcoma,lymphangiosarcoma, synoviosarcoma or mesotheliosarcoma, leukemias andlymphomas like granulocytic leukemia, monocytic leukemia, lymphocyticleukemia, malignant lymphoma, plasmocytoma, reticulum cell sarcoma orHodgkins disease, sarcomas like leiomysarcoma or rhabdomysarcoma,tumours of epithelial origin (Carcinomas) like squamous cell carcinoma,basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma,adenocarcinoma, papillary carcinoma, papillary adenocarcinoma,cystadenocarcinoma, medullary carcinoma, undifferentiated carcinoma,bronchogenic carcinoma, melanoma, renal cell carcinoma, hepatoma-livercell carcinoma, bile duct carcinoma-cholangiocarcinoma, papillarycarcinoma, transitional cell carcinoma, squamous cell carcinoma,choriocarcinoma, semonoma or embryonal carcinoma, tumours of the centralnervous system like glioma, meningoma, medulloblastoma, schwannoma orependymoma.

Moreover, the peptides according to the present invention also haveadvantageous properties for the treatment of chronic infections such asherpes, aphtous stomatitis and minimal change syndrome where clinicalimprovement has previously been reported by treatment with animmunostimulator such as Levamisole as well as other chronicinflammatory diseases in the urinary tract or in ear, nose or throut,which benefit from treatment with immunostimulators such as Biostim,Broncho-Vaxom and Ribomunyl, or at HIV infection or AIDS.

Moreover, an impairment, a defect or an imbalance of the immune responsehas also been postulated to exist at atopic diseases such as atopicdermatitis, rhinitis and asthma (Katz, D. H. Immunology Rewiews 41,77-108, 1977). Since theoretical considerations suggest that stimulationof an immune response would possibly be the best way of restoringimbalances and autoimmunity (Varela, F. J. and Coutinho, A. ImmunologyToday 12, 159-166, 1991), the peptides can also be expected to haveadvantageous properties for the treatment of asthma, rhinitis, atopicdermatitis and autoimmune diseases like non-obese diabetes, systemiclupus erythematosus, sclerodermia, Sjogren's syndrome, dermatomyositisor multiple sclerosis, rheumatoid arthritis and possibly psoriasis.

Moreover, the peptides according to the present invention, due to theirimmune modulating properties, may have advantageous properties asadjuvants in various forms of vaccine preparations. Due to their immunemodulating properties, the peptides can also be expected to havefavourable properties in inhibiting rejection of organs/transplants.

Finally, the peptides according to the present invention can be expectedto have advantageous properties in the treatment of artheriosclerosis,whether or not they will influence a putative inflammatory process inthis condition (Hansson. G. K. et al. Proc. Nat. Acad. Sci. USA 88,10530, 1991).

The peptides according to the present invention are particulary suitablefor treatment of malignancies such as melanoma, mammary carcinoma,gastrointestinal carcinoma, glioma, bladder carcinoma and squamous cellcarcinoma of the neck and head region; infections such as chronicbronchitis, hepatitis, post-infectious anergy and aquired immunedeficiencies such as AIDS; posttraumatic immunological anergy; andpurported autoimmune diseases such as rheumatoid arthritis, multiplesclerosis, artheriosclerosis and psoriasis.

Preparation

The peptides according to the present invention may be prepared usingthe standard solid phase sequential coupling technique utilizing anautomatic peptide synthesizer (see for example: Jones, J. The ChemicalSynthesis of Peptides, pp 132-156, first edition, Oxford UniversityPress, 1991 and R. Epton (ed) Innovation and Perspectives in Solid PhaseSynthesis, SPCC (UK) Ltd, 1990). The preparation starts form theC-terminal amino acid which can be obtained grafted to amethylbenzhydrylamine, benzhydrylamine or chloromethylated resin orother suitable solid support. The other amino acids are grafted step bystep, after having protected the side chains thereof. In this couplingmethod the α-amino groups of the amino acids are protected either withFmoc or t-Boc methodology.

Protective groups for the side chains of amino acids are well known inthe art. The whole protected peptide is released either from thechloromethylated resin by ammoniolysis to obtain the protected amide, orfrom the methylbenzhydrylamine or benzhydrylamine resins by acidolysis.

Peptides according to the invention may also be prepared using solutionmethods, by either stepwise or fragment condensations (see for example:Jones, J. The Chemical Synthesis of Peptides, pp 115-131, first edition,Oxford University Press, 1991). An appropriately alpha aminoprotectedamino acid is coupled to an appropriately alpha carboxyl protected aminoacid (such protection may not be required depending on the couplingmethod chosen) using diimides, symmetrical or unsymmetrical anhydrides,or other coupling reagents or techniques known to those skilled in theart. These techniques may be either chemical or enzymatic. The alphaamino and/or alpha carboxyl protecting groups are removed and the nextsuitably protected amino acid or block of amino acids are coupled toextend the growing peptide. Various combinations of protecting groupsand of chemical and/or enzymatic techniques and assembly strategies canbe used in each synthesis.

The dimers (peptides of the formulae (II), (III) and (IV)) and peptidescontaining intramolecular disulfide bonds between cysteine residues maybe prepared via general oxidation techniques described by Andreu et alin Methods in Molecular Biology, Peptide Synthesis Protocols vol 35(Humana Press Inc., Totowa, N.J., 1994) and Ruiz-Gayo et al, 1988,Tetrahedron Letters, 29, 3845-3848, as well as in other reference worksknown to those skilled in the art. Low-resolution mass spectra andaccurate mass determinations were recorded on an Autospec-Q, FisonsAnalytical, double focusing sector instrument equiped with a LSIMSinterface.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in more detail with the followingexamples which are not to be construed as limiting the invention.

EXAMPLE 1

Synthesis of H-Gly-Pro-Cys-Ile-OH (SEQ ID NO: 1)

A resin (0.37 g, 0.22 mequiv/g, 81 μmol) consisting of a crosslinkedpolystyrene backbone grafted with polyethyleneglycol chains,functionalized with the linker p-hydroxymethylphenoxyacetic acid(Sheppard and Williams, 1982, Int. J. Peptide Protein Res., 20, 451-454)and Fmoc-Ile, from Rapp Polymere (Germany) was used for the synthesis.N.sup.α -Fmoc amino acids were from Bachem (Switzerland), and Cys wasprotected with a triphenylmethyl (Trt) group. DMF was distilled beforebeing used.

The N.sup.α -Fmoc amino acids were coupled to the peptide-resin as7-aza-1-benzotriazolyl (HOAt) esters (Carpino, 1993, J. Am. Chem. Soc.115, 4397-4398). These were prepared, in situ, in the peptidesynthesizer from the appropriate N.sup.α -Fmoc amino acid (0.32 mmol)and HOAt (65 mg, 0.48 mmol) by addition of DMF (0.5 ml) and a solutionof 1,3-diisopropyl-carbodiimide in DMF (0.39 M, 0.8 ml, 0.312 mmol).After 45 min bromophenol blue (Flegel and Sheppard, 1990, J. Chem. Soc.,Chem. Commun. 536-538) in DMF (0.15mM, 0.4 ml) was added to the HOAtester by the synthesizer, and the resulting solution was recirculatedthrough the column. The acylation was monitored (Flegel and Sheppard,1990, J. Chem. Soc., Chem. Commun. 536-538) using the absorbance ofbromophenol blue at 600 nm, and when the coupling was complete thepeptide-resin was automatically washed with DMF. Coupling times fordifferent N.sup.α -Fmoc amino acids were approximately 30 min. N.sup.α-Fmoc deprotection of the peptide resin was performed by a flow of 20%piperidine in DMF through the column for 12.5 min, and was monitored(Dryland and Sheppard, 1986, J. Chem. Soc. Perkin Trans. I, 125-137)using the absorbance of the dibenzofulvene-piperidine adduct at 350 nm.After completion of the N.sup.α -Fmoc deprotection the peptide-resin wasagain washed automatically with DMF.

After completion of the synthesis and cleavage of the N-terminal N.sup.α-Fmoc group, the resin was washed with dichloromethane (5×5 ml) anddried under vacuum. The peptide (40 μmol) was then cleaved from theresin (200 mg), and the amino acid side chains were deprotected, bytreatment with trifluoroacetic acid-water-thioanisole-ethanedithiol(87.5:5 5:5:2.5, 20 ml) for 2 h, followed by filtration. Acetic acid (20ml) was added to the filtrate, the solution was concentrated, and aceticacid (20 ml) was added again before the solution was concentrated. Theresidue was dissolved in acetic acid-water (4:1, 25 ml) and the solutionwas freeze dried. The residue was triturated with ether (10 ml) whichgave a solid, crude peptide (21 mg) after drying under vacuum.

The peptide was analyzed on a Beckman System Gold HPLC using a KromasilC-8 column (1000 Å, 4.6×250 mm) and a linear gradient of 0-80% of B in Aover 60 min with a flow rate of 1.5 ml/min and detection at 214 nm(solvent systems A: 0.1% aqueous trifluoroacetic acid and B: 0.1%trifluoroacetic acid in acetonitrile). Purification of the crude peptide(21 mg) was performed with the same HPLC system on a 20×250 mm KromasilC-8 column with a flow rate of 11 ml/min and gave pure a product (8.5mg, 55%). FAB-MS: 389 (MH⁺).

The compound is also listed in table 1.

EXAMPLES 2-33

The peptides according to examples 2-33 were prepared using the sameprotocol as in example 1.

The compounds are listed in table 1.

EXAMPLE 34 ##STR5##

A solution of the monomer (1.5 mg/ml, in 50 nM phosphate buffer, pH=7.2)containing 5 ppm copper(II)-sulphate was stirred at room temperature for20 hours. The solution was lyophilized and redissolved inwater/acetonitrile (80/20) and purified by reverse phase HPLC using aVYDAC C-18 column (5 μm, 4×250 mm). An aqueous solution containing 0.1%trifluoroacetic acid and 5% acetonitrile was used as a mobile phase. Theconcentration of acetonitrile was increased linearly to 60% over a timescale of 25 min. The flow rate was 1.5 ml/min and the components weredetected with UV at 220 nm. Fractions were collected manually andchecked with FAB-MS. Repeated injections were pooled to give a solutionof the product which was lyophilized. FAB-MS: 1521 (MH⁺).

The compound is listed in table 1.

EXAMPLES 35-37

The peptides according to examples 35-37 were prepared using the sameprotocol as in example 34.

The compounds are listed in table 1.

EXAMPLE 38

The peptide according to example 38 was prepared using the same protocolas in example 1.

The compound is listed in table 1.

EXAMPLE 39

The peptide according to example 39 was prepared using the same protocolas in example 34-37.

The compounds are listed in table 1.

EXAMPLES 40-41

The peptides according to examples 40-41 were prepared using the sameprotocol as in example 1.

The compounds are listed in table 1.

EXAMPLE 42 ##STR6##

To prepare the parallel (head to head) homodimer a single peptide chainwith an Acm (acetamidomethyl) protecting group on one of the cysteinesand with the other cysteine unprotected(H-Phe-Cys-Leu-Gly-Pro-Cys(Acm)-Pro-OH) was synthesized using the sameprotocol as in example 1. The monomer was dimerized through oxidation ofthe free cysteines using the same protocol as in example 2. The seconddisulfide bond was accomplished using the protocol of Ruiz-Gayo(Ruiz-Gayo et al, 1988, Tetrahedron Letters, 29, 3845-3848) in which aonepot deprotection and oxidation of the Acm protected cysteine withiodine in 80% aqueous acetic acid resulted in a crude product which waspurified on HPLC.

The compound is listed in table 1.

EXAMPLE 43 ##STR7##

To prepare the antiparallel (head to tail) homodimer the generalprocedure of Ruiz-Gayo was used (Ruiz-Gayo et al, 1988, TetrahedronLetters, 29, 3845-3848). Two single peptide chains each with an Acm(acetamidomethyl) protecting group on one of the cysteines and with theother cysteine unprotected (H-Phe-Cys-Leu-Gly-Pro-Cys(Acm)-Pro-OH andH-Phe-Cys(Acm)-Leu-Gly-Pro-Cys-Pro-OH) was synthesized using the sameprotocol as in example 1. The unprotected cysteines on one of themonomers was activated with dithiopyridine resulting in the S-pyridylderivative H-Phe-Cys(SPyr)-Leu-Gly-Pro-Cys(Acm)-Pro-OH. This derivativewas reacted with the second peptide chain resulting in the firstdisulfide. The second disulfidebond was accomplished using the sameprotocol as in example 42 with iodine in 80% aqueous acetic acid which,after purification on HPLC, resulted in the final product.

The compound is listed in table 1.

The following Table 1 lists compounds according to the invention andtheir identification by FAB-MS spectra.

                  TABLE 1                                                         ______________________________________                                        Ex. No.                                                                             Peptide                 MH.sup.+ (m/z)                                  ______________________________________                                        1     H-Gly-Pro-Cys-Ile-OH (SEQ ID NO: 1)                                                                   389                                             2     Fmoc-Gly-Pro-Cys-IIe-OH (SEQ ID NO: 1)                                                                611                                             3     H-Gly-Pro-Cys-Gly-OH (SEQ ID NO: 2)                                                                   333                                             4     H-Ala-Pro-Cys-Ala-OH (SEQ ID NO: 3)                                                                   361                                             5     H-Ile-Pro-Cys-Tyr-OH (SEQ ID NO: 4)                                                                   495                                             6     H-Trp-Pro-Cys-Gly-OH (SEQ ID NO: 32)                                                                  462                                             7     H-Phe-Gly-Pro-Cys-Ile-OH (SEQ ID NO: 5)                                                               537                                             8     H-Gly-Pro-Cys-Ile-Leu-Asn-NH.sub.2                                                                    calcd: 615.329                                        (SEQ ID NO: 6)          (Exact miss)                                                                  found: 615.329                                  9     H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-OH                                                                      calcd: 762.422                                        (SEQ ID NO: 8)          (Exact mass)                                                                  found: 762.419                                  10    H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-OH                                                                      762                                                   (SEQ ID NO:8)                                                           11    H-Leu-Leu-Phe-Ala-Pro-Cys-Ile-OH                                                                      calcd: 776.438                                        (SEQ ID NO: 9)          (Exact mass)                                                                  found: 776.438                                  12    H-Leu-Leu-Phe-Arg-Pro-Cys-Ile-OH                                                                      861                                                   (SEQ ID NO: 10)                                                         13    H-Leu-Leu-Phe-Ile-Pro-Cys-Ile-OH                                                                      808                                                   (SEQ ID NO: 11)                                                         14    H-Leu-Leu-Phe-Asp-Pro-Cys-Ile-OH                                                                      819                                                   (SEQ ID NO: 12)                                                         15    H-Leu-Leu-Phe-Trp-Pro-Cys-Ile-OH                                                                      891                                                   (SEQ ID NO: 13)                                                         16    H-Leu-Leu-Phe-Gly-IIe-Cys-Ile-OH                                                                      778                                                   (SEQ ID NO: 14)                                                         17    H-Leu-Leu-Phe-Gly-Pec-Cys-Ile-OH                                                                      calcd: 776.438                                        (SEQ ID NO: 15)         (Exact mass)                                                                  found: 776.439                                  18    H-Ala-Val-Trp-Thr-Pro-Cys-Tyr-OH                                                                      839                                                   (SEQ ID NO: 33)                                                         19    H-Tyr-Phe-Tyr-Thr-Pec-Cys-Phe-OH                                                                      954                                                   (SEQ ID NO: 16)                                                         20    H-Phe-Val-Met-Ala-Pro-Cys-Phe-OH                                                                      814                                                   (SEQ ID NO: 17)                                                         21    H-Leu-Leu-Tyr-Ser-Pro-Cys-Phe-OH                                                                      842                                                   (SEQ ID NO: 18)                                                         22    H-Ile-Ser-Gly-Pro-Cys-Pro-Lys-OH                                                                      calcd: 701.384                                        (SEQ ID NO: 19)         (Exact mass)                                                                  found: 701.386                                  23    H-Phe-Leu-Phe-Gly-Pro-Cys-Ile-OH                                                                      796                                                   (SEQ ID NO: 20)                                                         24    H-Leu-Phe-Gly-Pro-Cys-Ile-Leu-NH.sub.2                                                                calcd: 761.438                                        (SEQ ID NO: 21)         (Exact mass)                                                                  found: 761.437                                  25    H-Glu-Lys-Gly-Pro-Cys-Tyr-Arg-OH                                                                      852                                                   (SEQ ID NO: 22)                                                         26    H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-OH                                                                  875                                                   (SEQ ID NO: 23)                                                         27    H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-NH.sub.2                                                            878                                                   (SEQ ID NO: 24)                                                         28    H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-OAllyl                                                              915.5                                                 (SEQ ID NO: 23)                                                         29    H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-NH.sub.2                                                        988                                                   (SEQ ID NO: 25)                                                         30    H-Phe-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-NH.sub.2                                                        calcd:                                                (SEQ ID NO: 27)         1022.550                                                                      (Exact mass)                                                                  found:                                                                        1022.551                                        31    H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-                                                            1517                                                  Leu-Met-Glu-NH.sub.2                                                          (SEQ ID NO: 28)                                                         32    H-Phe-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-                                                            1552                                                  Leu-Met-Glu-NH.sub.2                                                          (SEQ ID NO: 29)                                                         33    Fmoc-Phe-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-                                                             1776                                                  Arg-Leu-Met-Glu-NH.sub.2                                                      (SEQ ID NO: 29)                                                         34                                                                                   ##STR8##               1521                                                  (homodimer of SEQ ID NO: 8)                                             35                                                                                   ##STR9##               1682                                                  (homodimer of SEQ ID NO: 18)                                            36                                                                                   ##STR10##              775                                                   (homodimer of SEQ ID NO: 1)                                             37                                                                                   ##STR11##              3101                                                  Arg-Leu-Met-Glu-NH.sub.2                                                      Arg-Leu-Met-Glu-NH.sub.2                                                      (homodimer of SEQ ID NO: 29)                                            38    H-Phe-Cys-Leu-Gly-Pro-Cys-Pro-OH                                                                      736                                                   (SEQ ID NO: 30)                                                         39                                                                                   ##STR12##              734                                                   (SEQ ID NO: 31)                                                         40    H-Gly-Pro-Cys-Ile-Leu-Asn-Arg-OH                                                                      772                                                   (SEQ ID NO: 7)                                                          41    H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-                                                            1146                                                  OH (SEQ ID NO: 26)                                                      42                                                                                   ##STR13##              1467.7                                                (head to head homodimer of SEQ ID NO: 30)                               43                                                                                   ##STR14##              1468                                                  (head to tail homodimer of SEQ ID NO: 30)                               ______________________________________                                    

Pharmaceutical Preparations

The peptides according to the invention may be administered orally,nasally, rectally, intravenously or by inhalation.

The dosage will depend on the route of administration, the severity ofthe disease, age and weight of the patient and other factors normallyconsidered by the attending physician, when determining the individualregimen and dosage level as the most appropriate for a particularpatient.

The pharmaceutical preparations comprising the peptides according to theinvention may conveniently be tablets, pills, capsules, syrups, powdersor granules for oral administration sterile parenteral solutions orsuspensions for parenteral administration or suppositories for rectaladministration.

For the preparation of pharmaceutical preparations containing a peptideaccording to the present invention in the form of dosage units for oraladministration, the active peptide may be admixed with an adjuvant or acarrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such aspotato starch, corn starch or amylopectin, cellulose derivatives, abinder such as gelatine or polyvinylpyrrolidone, and a lubricant such asmagnesium stearate, calcium stearate, polyethylene glycol, waxes,paraffin, and the like, and then compressed into tablets. If coatedtablets are required, the cores, prepared as described above, may becoated with a concentrated sugar solution which may contain e.g. gumarabic, gelatine, talcum, titanium dioxide, and the like. Alternatively,the tablet may be coated with a polymer known to the man skilled in theart, dissolved in a readily volatile organic solvent or mixture oforganic solvents. Dyestuffs may be added to these coatings in order toreadily distinguish between tablets containing different activesubstances or different amounts of the active peptides.

For the preparation of soft gelatine capsules, the active substance maybe admixed with e.g. a vegetable oil or polyethylene glycol. Hardgelatine capsules may contain granules of the active substance usingeither the above mentioned excipients for tablets, e.g. lactose,saccharose, sorbitol , mannitol, starches (e.g. potato starch, cornstarch or amylopectin), cellulose derivatives or gelatine. Also liquidsor semisolids of the drug may be filled into hard gelatine capsules.

Dosage units for rectal application may be solutions or suspensions, ormay be prepared in the form of suppositories comprising the activesubstance in admixture with a neutral fatty base, or gelatin rectalcapsules comprising the active substance in admixture with vegetable oilor paraffin oil.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example solutions containing a peptide as hereindescribed as the active substance, the balance being sugar and a mixtureof ethanol, water, glycerol and propylene glycol. Optionally such liquidpreparations may contain colouring agents, flavouring agents, saccharineand carboxymethylcellulose as a thickening agent or other excipientsknown to the skilled man in art.

Solutions for parenteral applications by injection may be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substance. These solutions may also contain stabilizingagents and/or buffering agents and may involve the use of surface actingagents to improve solubility. They may conveniently be provided invarious dosage unit ampoules.

The compounds according to the invention may be formulated inpressurised metered dose inhalers or dry powder inhalers for oral ornasal inhalation or in liquid formulations for nebulisation. The activesubstance is micronised or otherwise processed to a particle sizesuitable for inhalation therapy (mass median diameter <4 μm).

For pressurised metered dose inhalers the micronized substance issuspended in a liquefied propellant or a mixture of liquefiedpropellants which also can act as solvents and filled into a containerwhich is equipped with a metering valve.

The propellants used may be hydrofluoroalkanes (HFAs) of differentcompositions. The most frequent used HFAs are tetrafluoroethane(propellant 134a) and heptafluoropropane (propellant 227).

Low concentrations of surfactants such as sorbitan trioleate, lecithin,oleic acid or other suitable substances may be used to improve thephysical stability of the preparation. Ethanol or other solvents may beused to increase the solubility of the substances in the propellants.

The active substance may also be delivered through a portable inhalerdevice suitable for dry powder inhalation. The active substance may beused alone or be combined with a suitable carrier substance such aslactose, mannitol or glucose. Other additives may also be included inthe powder formulation by various reasons, such as to increase thestability. The inhaler may be a single dose inhaler with onepredispensed dose or a multi dose inhaler in which the dose is createdby a metering unit within the inhaler or is delivered from an assemblyof predispensed doses.

Biological Studies

The ability of the peptides according to the invention to modulateimmune responses can be illustrated by its efficacy in the animaldelayed type hypersensitivity (DTH) test in mice.

Both male and female Balb/c mice, obtained from Bomholtsgaard (Denmark),were used with a weight of 18-20 gram.

4-Ethoxymethylene-2-phenyloxazolin-5-one (OXA) (England) and served asthe antigen in this test.

The mice were sensitized, Day 0, by epicutaneous application of 150 μlof an absolute ethanol-acetone (3:1) solution containing 3% OXA on theshaved abdomen. Treatment with the peptide or vehicle (0.9% NaCl) wasinitiated by oral feeding immediately after sensitization an continuedonce daily until Day 6. Seven days (Day 6) after the sensitization, bothears of all mice were challenged on both sides by topical application of20 μl 1% OXA dissolved in peanut oil. Ear thickness was measured priorto and 24 or 48 hours after challenge using an Oditest spring calliper.Challenges and measurements were performed under light pentobarbitalanaesthesia.

The intensity of the DTH reactions was expressed according to theformula: T_(t24/48) -T_(t0) μm units, where t0, t24 and t48 representthe ear thickness before and 24 or 48 hours after challengerespectively, in individual tests (T). The result were expressed as themean ±S.E.M. The level of significance between means of the groups wasobtained by Student's two-tailed t-test. The immunomodulating effect ofthe peptide is reflected in a significant difference in the increase ordecrease in ear thickness as compared to the control.

DISCUSSION

The present invention describes peptides that can be expected to havefavorable effects for the treatment of various diseases, affecting theimmune system including diseases where an anergy of the immune response,an aberrant immune response or peripheral tolerance to pathogenes or anineffective host defence by other reasons can be suspected. These typeof drugs have an urgent need on the market, instead of or as acomplement to present more toxic drugs, for the treatment of manydiseases.

    ______________________________________                                        Abbreviations                                                                 ______________________________________                                        Pec         pipecolic acid                                                    Ac          acetyl                                                            Fmoc        9-fluorenylmethyl carbamate                                       Bpoc        1-methyl-1-(4-biphenylyl)ethyl carbamate                          Trt         trityl                                                            Alloc       allyl carbamate                                                   Boc         t-butyl carbamate                                                 FAB-MS      fast atom bombardment mass spectrometry                           DTH         delayed type hypersensitivity                                     OXA         4-ethoxymethylene-2-phenyloxazolin-5-one                          Acm         acetamidomethyl                                                   ______________________________________                                    

    __________________________________________________________________________    #             SEQUENCE LISTING                                                - (1) GENERAL INFORMATION:                                                    -    (iii) NUMBER OF SEQUENCES: 39                                            - (2) INFORMATION FOR SEQ ID NO:1:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 4 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                 - Gly Pro Cys Ile                                                              1                                                                            - (2) INFORMATION FOR SEQ ID NO:2:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 4 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                 - Gly Pro Cys Gly                                                              1                                                                            - (2) INFORMATION FOR SEQ ID NO:3:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 4 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                 - Ala Pro Cys Ala                                                              1                                                                            - (2) INFORMATION FOR SEQ ID NO:4:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 4 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                 - Ile Pro Cys Tyr                                                              1                                                                            - (2) INFORMATION FOR SEQ ID NO:5:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 5 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                 - Phe Gly Pro Cys Ile                                                          1               5                                                            - (2) INFORMATION FOR SEQ ID NO:6:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 6 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 6...6                                                 #where Xaa at position 6 is "Asn-NH2"                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                 - Gly Pro Cys Ile Leu Xaa                                                      1               5                                                            - (2) INFORMATION FOR SEQ ID NO:7:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                 - Gly Pro Cys Ile Leu Asn Arg                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:8:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                 - Leu Leu Phe Gly Pro Cys Ile                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:9:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                 - Leu Leu Phe Ala Pro Cys Ile                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:10:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                                - Leu Leu Phe Arg Pro Cys Ile                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:11:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                                - Leu Leu Phe Ile Pro Cys Ile                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:12:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                                - Leu Leu Phe Asp Pro Cys Ile                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:13:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                                - Leu Leu Phe Trp Pro Cys Ile                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:14:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                                - Leu Leu Phe Gly Ile Cys Ile                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:15:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 5...5                                                 #where Xaa at position 5 is "pipecolic acid"                                  -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                                - Leu Leu Phe Gly Xaa Cys Ile                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:16:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 5...5                                                 #where Xaa at position 5 is "pipecolic acid"                                  -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                                - Tyr Phe Tyr Thr Xaa Cys Phe                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:17:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                                - Phe Val Met Ala Pro Cys Phe                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:18:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                                - Leu Leu Tyr Ser Pro Cys Phe                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:19:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                                - Ile Ser Gly Pro Cys Pro Lys                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:20:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                                - Phe Leu Phe Gly Pro Cys Ile                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:21:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 7...7                                                 #where Xaa at position 7 is "Leu-NH2"                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                                - Leu Phe Gly Pro Cys Ile Xaa                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:22:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:                                - Glu Lys Gly Pro Cys Tyr Arg                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:23:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:                                - Leu Leu Phe Gly Pro Cys Ile Leu                                              1               5                                                            - (2) INFORMATION FOR SEQ ID NO:24:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 8...8                                                 #where Xaa at position 8 is "Leu-NH2"                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:                                - Leu Leu Phe Gly Pro Cys Ile Xaa                                              1               5                                                            - (2) INFORMATION FOR SEQ ID NO:25:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 9...9                                                 #where Xaa at position 9 is "Asn-NH2"                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:                                - Leu Leu Phe Gly Pro Cys Ile Leu Xaa                                          1               5                                                            - (2) INFORMATION FOR SEQ ID NO:26:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:                                - Leu Leu Phe Gly Pro Cys Ile Leu Asn Arg                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:27:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 9...9                                                 #where Xaa at position 9 is "Asn-NH2"                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:                                - Phe Leu Phe Gly Pro Cys Ile Leu Xaa                                          1               5                                                            - (2) INFORMATION FOR SEQ ID NO:28:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 13...13                                               #where Xaa at position 13 is "Glu-NH2"                                        -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:                                - Leu Leu Phe Gly Pro Cys Ile Leu Asn Arg Le - #u Met Xaa                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:29:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Other                                                           (B) LOCATION: 13...13                                               #where Xaa at position 13 is "Glu-NH2"                                        -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:                                - Phe Leu Phe Gly Pro Cys Ile Leu Asn Arg Le - #u Met Xaa                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:30:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:                                - Phe Cys Leu Gly Pro Cys Pro                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:31:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:                                - Phe Cys Leu Gly Pro Cys Pro                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:32:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 4 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:                                - Trp Pro Cys Gly                                                              1                                                                            - (2) INFORMATION FOR SEQ ID NO:33:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:                                - Ala Val Trp Thr Pro Cys Tyr                                                  1               5                                                            - (2) INFORMATION FOR SEQ ID NO:34:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:                                - Leu Glu Cys Gly Pro Cys Phe Leu                                              1               5                                                            - (2) INFORMATION FOR SEQ ID NO:35:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:                                - Leu Cys Ala Gly Pro Cys Phe Leu                                              1               5                                                            - (2) INFORMATION FOR SEQ ID NO:36:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 14 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:                                - Tyr Ile Pro Cys Phe Pro Ser Ser Leu Lys Ar - #g Leu Leu Ile                 #                10                                                           - (2) INFORMATION FOR SEQ ID NO:37:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:                                - Tyr Ile Pro Cys Phe Pro Ser Ser Leu Lys Ar - #g Leu Ile                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:38:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:                                - Ser Gly Pro Cys Pro Lys Asp Gly Gln Pro Se - #r                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:39:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:                                - Thr Pro Pro Thr Pro Cys Pro Ser                                              1               5                                                            __________________________________________________________________________

We claim:
 1. A homodimer of a peptide comprising 4-15 amino acidsaccording to Formula II: A-X-Y-Cys-Z-B (II) | A-X-Y-Cys-Z-Bwherein X isGly, Y is Pro and Z is Ile; X is Gly, Y is Pro and Z is Gly; X is Ala, Yis Pro and Z is Ala; X is Ile, Y is Pro and Z is Tyr; X is Ala, Y is Proand Z is Ile; X is Arg, Y is Pro and Z is Ile; X is Ile, Y is Pro and Zis Ile; X is Asp, Y is Pro and Z is Ile; X is Trp, Y is Pro and Z isIle; X is Trp, Y is Pro and Z is Gly; X is Gly, Y is Ile and Z is Ile; Xis Gly, Y is Pec and Z is Ile; X is Thr, Y is Pro and Z is Tyr; X isThr, Y is Pec and Z is Phe; X is Ala, Y is Pro and Z is Phe; X is Ser, Yis Pro and Z is Phe; X is Gly, Y is Pro and Z is Pro; or X is Gly, Y isPro and Z is Tyr; and A is H, an N-terminal protecting group, or atleast one amino acid in either L-form or D-form, with or withoutprotected side chain-functionality and with or without N-terminalprotection; and B is OH, NH₂, a C-terminal protecting group, or at leastone amino acid in either L-form or D-form, with or without protectedside chain-functionality and ending with a C-terminal amide, a freecarboxyl group, or a protecting group; provided a homodimer of thepeptide Pro-Cys-Pro-Lys-Asp-Gly-Gln-Pro-Ser (SEQ ID NO:38) is exceptedfrom Formula II.
 2. The homodimer of claim 1, whereinX is Gly, Y is Proand Z is Ile; X is Ala, Y is Pro and Z is Ile; X is Arg, Y is Pro and Zis Ile; X is Asp, Y is Pro and Z is Ile; X is Trp, Y is Pro and Z isIle; X is Ser, Y is Pro and Z is Phe; or X is Gly, Y is Pro and Z isPro.
 3. The homodimer of claim 1, whereinA is H, an N-terminalprotecting group, an amino acid in either L-form or D-form selected fromthe group consisting of Phe, Leu, Met, Ser, Lys and Tyr, with or withoutprotected side chain-functionality and with or without an N-terminalprotecting group, or an amino acid sequence having Phe, Leu, Met, Ser,Lys or Tyr as the most C-terminal amino acid in the sequence, with orwithout protected side chain-functionalities and with or without anN-terminal protecting group, wherein the N-terminal protecting group isselected from the group consisting of an acetyl group (Ac), a9-fluorenylmethyl carbamate group (Fmoc), a1-methyl-1-(4-biphenylyl)ethyl carbamate group (Bpoc), a trityl group(Trt), an allyl carbamate group (Alloc) and a t-butyl carbamate group(Boc); and B is OH, NH₂, a C-terminal protecting group, an amino acid ineither L-form or D-form selected from the group consisting of Leu, Lysor Arg, with or without protected sidechain-functionality and endingwith a C-terminal amide, a free carboxyl group, or a C-terminalprotecting group, or an amino acid sequence having Leu, Lys or Arg, asthe most N-terminal amino acid of the sequence, with or withoutprotected sidechain-functionalities and ending with a C-terminal amide,a free carboxyl group, or a C-terminal protecting group, wherein theC-terminal protecting group is selected from the group consisting of aC₁ -C₆ alkyl group, an allyl group, an adamantyl group, a benzyl group,and a t-butyl group; provided a homodimer of the peptidePro-Cys-Pro-Lys-Asp-Gly-Gln-Pro-Ser (SEQ ID NO:38) is excepted fromFormula II.
 4. A homodimer selected from the group consistingofH-Gly-Pro-Cys-Ile-OH |H-Gly-Pro-Cys-Ile-OH (homodimer of SEQ IDNO:1);Fmoc-Gly-Pro-Cys-Ile-OH |Fmoc-Gly-Pro-Cys-Ile-OH (homodimer of SEQID NO:1);H-Gly-Pro-Cys-Gly-OH |H-Gly-Pro-Cys-Gly-OH (homodimer of SEQ IDNO:2);H-Ala-Pro-Cys-Ala-OH |H-Ala-Pro-Cys-Ala-OH (homodimer of SEQ IDNO:3);H-Ile-Pro-Cys-Tyr-OH |H-Ile-Pro-Cys-Tyr-OH (homodimer of SEQ IDNO:4);H-Trp-Pro-Cys-Gly-OH |H-Trp-Pro-Cys-Gly-OH (homodimer of SEQ IDNO:32);H-Phe-Gly-Pro-Cys-Ile-OH |H-Phe-Gly-Pro-Cys-Ile-OH (homodimer ofSEQ ID NO:5);H-Gly-Pro-Cys-Ile-Leu-Asn-NH₂|H-Gly-Pro-Cys-Ile-Leu-Asn-NH₂ (homodimer of SEQ IDNO:6);H-Gly-Pro-Cys-Ile-Leu-Asn-Arg-NH₂|H-Gly-Pro-Cys-Ile-Leu-Asn-Arg-NH₂ (homodimer of SEQ IDNO:7);H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-OH |H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-OH(homodimer of SEQ ID NO:8);H-Leu-Leu-D-Phe-Gly-Pro-Cys-Ile-OH|H-Leu-Leu-D-Phe-Gly-Pro-Cys-Ile-OH (homodimer of SEQ IDNO:8);H-Leu-Leu-Phe-Ala-Pro-Cys-Ile-OH |H-Leu-Leu-Phe-Ala-Pro-Cys-Ile-OH(homodimer of SEQ ID NO:9);H-Leu-Leu-Phe-Arg-Pro-Cys-Ile-OH|H-Leu-Leu-Phe-Arg-Pro-Cys-Ile-OH (homodimer of SEQ IDNO:10);H-Leu-Leu-Phe-Ile-Pro-Cys-Ile-OH|H-Leu-Leu-Phe-Ile-Pro-Cys-Ile-OH (homodimer of SEQ IDNO:11);H-Leu-Leu-Phe-Asp-Pro-Cys-Ile-OH|H-Leu-Leu-Phe-Asp-Pro-Cys-Ile-OH (homodimer of SEQ IDNO:12);H-Leu-Leu-Phe-Trp-Pro-Cys-Ile-OH|H-Leu-Leu-Phe-Trp-Pro-Cys-Ile-OH (homodimer of SEQ IDNO:13);H-Leu-Leu-Phe-Gly-Ile-Cys-Ile-OH|H-Leu-Leu-Phe-Gly-Ile-Cys-Ile-OH (homodimer of SEQ IDNO:14);H-Leu-Leu-Phe-Gly-Pec-Cys-Ile-OH|H-Leu-Leu-Phe-Gly-Pec-Cys-Ile-OH (homodimer of SEQ IDNO:15);H-Ala-Val-Trp-Thr-Pro-Cys-Tyr-OH|H-Ala-Val-Trp-Thr-Pro-Cys-Tyr-OH (homodimer of SEQ IDNO:33);H-Tyr-Phe-Tyr-Thr-Pec-Cys-Phe-OH|H-Tyr-Phe-Tyr-Thr-Pec-Cys-Phe-OH (homodimer of SEQ IDNO:16);H-Phe-Val-Met-Ala-Pro-Cys-Phe-OH|H-Phe-Val-Met-Ala-Pro-Cys-Phe-OH (homodimer of SEQ IDNO:17);H-Leu-Leu-Tyr-Ser-Pro-Cys-Phe-OH|H-Leu-Leu-Tyr-Ser-Pro-Cys-Phe-OH (homodimer of SEQ IDNO:18);H-Ile-Ser-Gly-Pro-Cys-Pro-Lys |H-Ile-Ser-Gly-Pro-Cys-Pro-Lys-OH(homodimer of SEQ ID NO:19);H-Phe-Leu-Phe-Gly-Pro-Cys-Ile-OH|H-Phe-Leu-Phe-Gly-Pro-Cys-Ile-OH (homodimer of SEQ IDNO:20);H-Leu-Phe-Gly-Pro-Cys-Ile-Leu-NH₂|H-Leu-Phe-Gly-Pro-Cys-Ile-Leu-NH₂ (homodimer of SEQ IDNO:21);H-Glu-Lys-Gly-Pro-Cys-Tyr-Arg-OH|H-Glu-Lys-Gly-Pro-Cys-Tyr-Arg-OH (homodimer of SEQ IDNO:22);H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-OH|H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-OH (homodimer of SEQ IDNO:23);H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-NH₂|H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-NH₂ (homodimer of SEQ IDNO:24);H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-OAllyl|H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-OAllyl (homodimer of SEQ IDNO:23);H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-NH₂|H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-NH₂ (homodimer of SEQ IDNO:25);H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-OH|H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-OH (homodimer of SEQ IDNO:26);H-Phe-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-NH₂|H-Phe-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-NH₂ (homodimer of SEQ IDNO:27);H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-Leu-Met-Glu-NH₂|H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-Leu-Met-Glu-NH₂ (homodimer ofSEQ ID NO:28);H-Phe-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-Leu-Met-Glu-NH₂|H-Phe-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-Leu-Met-Glu-NH₂ (homodimer ofSEQ ID NO:29);andFmoc-Phe-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-Leu-Met-Glu-NH₂|Fmoc-Phe-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-Leu-Met-Glu-NH₂ (homodimerof SEQ ID NO:29).
 5. A homodimer selected from the group consistingof:H-Gly-Pro-Cys-Ile-OH |H-Gly-Pro-Cys-Ile-OH (homodimer of SEQ IDNO:1);H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-OH |H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-OH(homodimer of SEQ ID NO:8);H-Leu-Leu-Tyr-Ser-Pro-Cys-Phe-OH|H-Leu-Leu-Tyr-Ser-Pro-Cys-Phe-OH (homodimer of SEQ ID NO:18);andH-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-Leu-Met-Glu-NH₂|H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-Leu-Asn-Arg-Leu-Met-Glu-NH₂ (homodimer ofSEQ ID NO:28).
 6. A homodimer selected from the group consistingof:H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-OH |H-Leu-Leu-Phe-Gly-Pro-Cys-Ile-OH(homodimer of SEQ ID NO:8); andH-Leu-Leu-Tyr-Ser-Pro-Cys-Phe-OH|H-Leu-Leu-Tyr-Ser-Pro-Cys-Phe-OH (homodimer of SEQ ID NO:18).
 7. Apharmaceutical composition comprising the homodimer of claim 2 and apharmaceutically acceptable carrier.
 8. A homodimer of claim 3 whereinXis Gly, Y is Pro and Z is Ile; X is Ala, Y is Pro and Z is Ile; X isArg, Y is Pro and Z is Ile; X is Asp, Y is Pro and Z is Ile; X is Trp, Yis Pro and Z is Ile; X is Ser, Y is Pro and Z is Phe; or X is Gly, Y isPro and Z is Pro.
 9. A pharmaceutical composition comprising thehomodimer of claim 2 and a pharmaceutically acceptable carrier.
 10. Apharmaceutical composition comprising the homodimer of claim 3 and apharmaceutically acceptable carrier.
 11. A pharmaceutical compositioncomprising the homodimer of claim 4 and a pharmaceutically acceptablecarrier.
 12. A pharmaceutical composition comprising the homodimer ofclaim 5 and a pharmaceutically acceptable carrier.
 13. A pharmaceuticalcomposition comprising the homodimer of claim 6 and a pharmaceuticallyacceptable carrier.
 14. A pharmaceutical composition comprising thehomodimer of claim 8 and a pharmaceutically acceptable carrier.